The present invention relates to a use of indole-3-propionic acid and, more particularly, to the use of indole-3-propionic acid to prevent cytotoxic effects of amyloid beta protein, to treat fibrillogenic diseases, to decrease oxidation in biological samples, and to treat diseases or other conditions where free radicals and/or oxidative stress play a role.
It is estimated that ten percent of persons older than 65 years of age have mild to severe dementia. Alzheimer""s Disease (xe2x80x9cADxe2x80x9d) is the most common cause of chronic dementia with approximately two million people in the United States having the disease. Although once considered a condition of middle age, it is now known that the histopathologic lesions of Alzheimer""Disease (i.e., neuritic amyloid plaques, neurofibrillary degeneration, and granulovascular neuronal degeneration) are also found in the brains of elderly people with dementia. The number of such lesions correlates with the degree of intellectual deterioration. This high prevalence, combined with the rate of growth of the elderly segment of the population, make dementia (and particularly AD) one of the most important current public health problems.
Deposition of cerebral amyloid is a primary neuropathologic marker of Alzheimer""Disease. The amyloid is composed of a 40-42 amino acid peptide called the amyloid beta protein (xe2x80x9cAxcex2xe2x80x9d) (Glenner and Wong, 1984). Amyloid deposits in AD are found mainly as components of senile plaques, and in the walls of cerebral and meningeal blood vessels (Robakis and Pangalos, 1994).
Molecular cloning showed that AP comprises a small region of a larger amyloid precursor protein (xe2x80x9cAPPxe2x80x9d) (Robakis et al., 1987; Weidemann et al., 1989). Briefly, this is a type I integral membrane glycoprotein having a large extracytoplasmic portion, a smaller intracytoplasmic region, and a single transmembranous domain. APP undergoes extensive post-translational modifications (Pappolla and Robakis, 1995; Robakis and Pangalos, 1994) prior-to the secretion of its N-terminal portion (Sambamurti et al., 1992; Robakis and Pangalos, 1994). Physiologic processing of APP involves cleavage within the Axcex2 sequence by an unidentified enzyme, alpha-secretase (Anderson et al., 1991). Smaller quantities of APP molecules are cleaved at two other sites that could potentially produce amyloidogenic secreted or membrane bound APP (Robakis and Pangalos, 1994). Axcex2 is also produced during normal cellular metabolism (Haass et al., 1992; Shoji et al., 1992).
There is some controversy as to whether amyloid causes AD; however, three main lines of evidence have strengthened the amyloid hypothesis. The first piece of evidence is provided by the identification of several point mutations within the APP gene. These mutations segregate within a subgroup of patients afflicted with a familial form of the disorder and thus suggest a pathogenetic relationship between the APP gene and AD (Chartier-Harlin et al., 1991; Kennedy et al., 1993). Secondly, amyloid deposition temporally precedes the development of neurofibrillary changes (Pappolla et al., 1996) and this observation is also consistent with a link between amyloid and neuronal degeneration. Finally, it has been shown that Axcex2 is toxic to neurons (Yankner et al., 1990; Behl et al., 1992; Behl et al., 1994; Zhang et al., 1994), a finding that also strengthened the hypothesis that the amyloid peptide may contribute to the neuronal pathology in AD.
The finding that Axcex2 has neurotoxic properties has provided a possible connection between amyloid accumulation and neurodegeneration. Because of the close association between aging and AD and the similarities in the neuropathology of both conditions, oxidative stress has been proposed to play a role in the pathogenesis of AD lesions.
Several investigators demonstrated that oxygen free-radicals (xe2x80x9cOFRsxe2x80x9d) are related to the cytotoxic properties of Axcex2 (Behl, 1992; Behl, 1994; Harris et al., 1995; Butterfield et al., 1994; Goodman and Mattson, 1994). Such findings are important, since markers of oxidative injury are topographically associated with the neuropathologic lesions of AD (Pappolla et al., 1992; Furuta et al., 1995; Smith et al., 1995; Pappolla et al., 1996). Because of these observations, antioxidants have been proposed as potential therapeutic agents in AD (Mattson, 1994; Hensley et al., 1994; Pappolla et al., 1996).
A need continues for methods of treating AD and other fibrillogenic diseases.
The present invention relates to a method of preventing cytotoxic effects of amyloid beta protein on cells. The method includes contacting the cells with an effective amount of an indole-3-propionic acid or an ester or salt thereof.
The present invention further relates to a method of treating a fibrillogenic disease in a human subject. The method includes administering, to the human subject, an amount of indole-3-propionic acid or an ester or salt thereof effective to inhibit or reverse fibrillogenesis.
The present invention also relates to a method of decreasing oxidation in a biological sample. The method includes contacting the biological sample with an effective amount of a indole-3-propionic acid or a salt or ester thereof.
The present invention still further relates to a method of treating diseases or other conditions where free radicals and/or oxidative stress play a role. The method includes administering, to the human subject, an amount of indole-3-propionic acid or an ester or salt thereof effective to treat such disease or condition.